Dexmedetomidine protects rats from postoperative cognitive dysfunction via regulating the GABAB R-mediated cAMP-PKA-CREB signaling pathway.

This work attempts to discuss whether dexmedetomidine (Dex) can protect rats from postoperative cognitive dysfunction (POCD) through regulating the γ-aminobutyric acid-B receptor (GABAB R)-mediated cyclic adenosine monophosphate (cAMP) - protein kinase A (PKA) - cAMP-response element binding (cAMP-PKA-CREB) signaling pathway. Sprague-Dawley rats were divided into a non-surgical group (Control), a surgical group (Model), a surgical group treated with Dex (Model + Dex), a surgical group treated with GABAB R antagonist (Model + CGP 35348) and a surgical group treated with Dex and GABAB R agonist (Model + Dex + Baclofen). Cognitive and memory functions were evaluated by Y-maze test and open-field test. The neuronal morphology of the hippocampus was observed by hematoxylin and eosin staining and neuronal apoptosis was by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling method. Inflammatory factors and cAMP levels were detected by enzyme-linked immunosorbent assay while expressions of GABAB R and PKA-CREB pathway-related molecules by Western blot. Compared with control rats, the model rats exhibited reduced alternation rates with a prolonged time spent in the central zone; meanwhile, levels of tumor necrosis factor-α and interleukin-1ß and the apoptotic index, as well as GABAB R1 and GABAB R2 expressions were increased in the model rats, but the cAMP-PKA-CREB pathway was inhibited (all P < 0.05). When treated with either Dex or CGP 35348, the surgical rats displayed an opposite tendency concerning the above factors as compared to the model rats (all P < 0.05). Furthermore, Baclofen, the agonist of GABAB R, could reverse the protective effect of Dex against POCD in rats. Dex protects rats from POCD possibly via suppressing GABAB R to up-regulate the cAMP-PKA-CREB signaling pathway, thereby alleviating the hippocampal inflammation caused by surgical trauma.

Dexmedetomidine reduces the apoptosis of rat hippocampal neurons via mediating ERK1/2 signal pathway by targeting miR-155.

Rat hippocampal neurons were isolated and divided into Normal, oxygen glucose deprivation/reoxygenation (OGD/R), OGD/R + DEX, OGD/R + NC mimic, OGD/R + miR-155 mimic and OGD/R + DEX + miR-155 mimic groups. In OGD/R group, LDH, ROS and MDA levels and apoptosis rate was increased, with up-regulations of miR-155, Cyt c and Bax/Bcl-2 ratio, but decreases of SOD, GSH-Px and MMP levels, as well as down-regulations of p-ERK1/2/ERK1/2. As compared to the OGD/R group, parameters above in the OGD/R + DEX group were ameliorated evidently, while OGD/R + miR-155 mimic group manifested the opposite changes. Besides, miR-155 mimic could abolish the protective effect of DEX on the hippocampal neurons under OGD/R. DEX, via down-regulating the expression of miR-155, could activate the ERK1/2 pathway, thereby mitigating the apoptosis and oxidative stress injury and increasing the MMP, thereby protecting hippocampal cells from OGD/R injury.